Synthetic Peptides Deried From Spider Toxin, Gsmtx4, Reduce Mechanical And Neuropathic Pain

The peptide GsMTx-4, extracted from the venom of Grammostola spatulata, has been widely used to identify mechanosensitive (MS) channels in sensory neuron, it was reported having effect on reducing the mechanical hyperalgesia and neuropathic pain in rats recently. GsMTx4 belongs to inhibitor cysteine knots (ICK) peptides and has six cysteines that forms 4 loops. It also possess a hydrophobic face that is proposed to promote interfacial adsorption into the lipid bilayer for performing its function. To investigate the role of the loops as well as identify core amino acid in the loop, we synthetized a variety of peptide mimetics of GsMTx4 to test their inhibitory effects on hyperalgesia. We showed that intraperitoneal injection of the synthesized mimetics which contains the main amino acids in loop2 and loop3 in GsMTx4 significantly increased the mechanical threshold for paw withdrawal in Randall Sellito test, eliciting significant analgesic responses to inflammation-induced mechanical hyperalgesia in the similar way as full length of GsMTx4 does. These synthetic mimetics also reduced mechanical allodynia induced by inflammation and by sciatic nerve injury. However, these synthetic peptides were ineffective at changing the withdrawal latency of hot plate and tail-flick tests. Furthermore, substitution of cysteines in the mimetics reduces or even eliminates the effects on hyperalgesia. In a similar way, mutation of the hydrophobic residues also abolishes the analgesic effect on rats. These results suggest that the mimetics selectively alleviate mechanical hyperalgesia. In addition, both the cysteines and the hydrophobic residues in the peptides play essential roles for inhibitory function on pain.